Chronic exposure to solar ultraviolet (UV) radiation, particularly UVB (290-320 nm), is primarily responsible for more than 1,000,000 new cases of nonmelanoma skin cancer each year in the USA alone, making it the most hazardous environmental carcinogen known for humans. Thus, there is an urgent need to develop strategies to prevent the occurrence of cutaneous malignancies. It is well documented that UV radiation is a potent producer of reactive oxygen species (ROS), which play a critical role in cellular signal transduction pathways. Phosphorylation of cell signaling molecules is implicated in various skin diseases including skin cancer. One approach to reduce the risk of UV-induced ROS-mediated skin cancer is the use of antioxidant agents. Several studies led to a strong suggestion that the regular intake of polyphenolic antioxidants from green tea may be an appropriate and effective strategy to prevent some forms of human cancers. We and others have shown that a potyphenolic fraction isolated from green tea, and particularly its major and the most effective chemopreventive antioxidant constituent (-)-epigallocatechin-3-gallate (EGCG) has remarkable preventive effects against UV-induced skin carcinogenesis in mouse model. We found that treatment with EGCG to human skin before UV exposure inhibits UV-induced oxidative stress. The aim of this application is to defme the mechanism through which EGCG would prevent UV-induced oxidative stress-mediated cell signaling pathways in human skin. The central hypothesis to be tested in this proposal is that UV-induced oxidative stress causes phosphorylation of epidermal growth factor receptor (EGFR), and mitogen-activated protein kinases (MAPK), such as extracellular signal-regulated kinase (ERK1/2) and p38 in human skin. The corollary to our hypothesis is that topical treatment with EGCG before UV exposure of the skin will prevent UV radiation-induced oxidative stress, which in turn will inhibit oxidative stress-mediated phosphorylation of cellular signaling events. The inhibition of UV-induced oxidative stress- mediated signaling pathways by EGCG will prevent the occurrence of skin cancer. Validation of this hypothesis would have major implications for the importance of oxidative stress-mediated skin cancer, as well as offering promise for the development of novel intervention approaches to mitigate UV-induced cellular signaling events linked to skin cancer incidence by the use of antioxidants.